Project Summary: Mutations in nuclear lamins are the source of phenotypically diverse genetic disorders known as laminopathies, which include dilated cardiomyopathies, muscular dystrophy, neuropathy and premature aging syndromes. Lamins are constituent of nuclear envelope therefore it is intriguing how altered function of a nuclear structural components lead to such a wide range of diseases. Understanding nuclear lamina interaction with structural proteins, chromatin, transcription factors, and other signaling partners has provided some insight in the disease mechanism. However novel molecular component and mechanistic details that lead to such tissue specific disease phenotypes in laminopathies are not understood yet. In work leading to the proposed research, by studying the human heart with an LMNA mutation, an LMNA-deficient (Lmna-/-) DCM mouse model, and isolated cardiac myocyte transcriptomic analysis, we identified a diverse set of differentially expressed gene in laminopathies and specifically identified KDM5A and B (or KDM5) as most induced upstream regulator of gene dysregulation. KDM5 is a histone demethylase that removes tri- and di-methylations of lysine 4 of histone H3 (H3K4me3), often leading to suppression of gene expression. The role of KDM5 in heart and in laminopathies has not been documented so far. Our preliminary data point to a potential novel role of KDM5 in the pathogenesis of laminopathies. Therefore to further determine the causal relation of KDM5 in laminopathies we re-expressed LmnaWT in Lmna-/- mouse (by AAV9) and found that this was associated with rescue in the KDM5 network and decreased apoptosis and increased overall survival. Hence, we propose that KDM5 induction affects cardiac function, survival and is pathogenic in the context of laminopathies. To ascertain the elusive role of KDM5 in heart and determine if induction of KDM5 is actually pathogenic or rather beneficial, we propose two specific Aims. In the Aim 1 we will investigate the consequence of AAV9-shRNA-mediated knockdown of KDM5A and B individually or together in cardiomyocytes of Lmna-/- mice. We will follow the disease progression by monitoring cardiac function and survival upon KDM5 knockdown. In the Aim 2 we will use chemical inhibition approach to suppress KDM5 activity and monitor its effect on cardiac function and survival. By using these complementary approaches we will be able to determine if Induction of KDM5 in laminopathies is pathogenic or beneficial /compensatory. The studies will provide novel insight in the yet unknown biological function(s) of KDM5 in heart and provide a platform for future mechanistic studies and opportunity for a therapeutic intervention in laminopathies.